P1027: RESPONSES TO AVAPRITINIB IN PATIENTS WITH ADVANCED SYSTEMIC MASTOCYTOSIS: HISTOPATHOLOGIC ANALYSES FROM EXPLORER AND PATHFINDER CLINICAL STUDIES
Authors: T. George, K. H. Karner, K. A. Moser, A. Rets, A. Reiter, D. H. Radia, M. Deininger, H.-M. Lin, S. Dimitrijević, D. J. DeAngelo
Journal: HemaSphere (2022)

Background: Systemic mastocytosis (SM) is a mast cell (MC) neoplasm driven by the KIT D816V mutation in ~95% of cases. Diagnosis includes evaluation of MC aggregates in extracutaneous organs, atypical MC morphology, and MC immunophenotype. Avapritinib, a potent and selective KIT D816V inhibitor, has been approved in the US for patients with advanced SM (AdvSM) based on the phase 1 EXPLORER and phase 2 PATHFINDER studies. Aims: Here, we describe a comprehensive evaluation of the effect of avapritinib on bone marrow (BM) pathology in patients treated in these studies. Methods: Patients aged ≥18 years with diagnoses of AdvSM per local investigator were treated with once-daily avapritinib <200 mg (n=17), 200 mg (n=126), and ≥300 mg (n=50). Bone marrow biopsies (BMBs), aspirates (BMAs), and peripheral blood (PB) smears were obtained at screening, and after 8 and 24 weeks of treatment with avapritinib. Evaluations were performed using standard Wright-Giemsa and H&E staining, and IHC was performed on formalin-fixed EDTA-decalcified BMBs using standard techniques for CD25 and CD30. Changes in fibrosis were assessed by the European Consensus on grading of BM fibrosis (MF score). Results: As of April 2021, 193 patients enrolled in EXPLORER (n=86) and PATHFINDER (n=107) were included in analyses with centrally confirmed diagnoses of aggressive SM (n=29), SM with an associated hematologic neoplasm (n=119), mast cell leukemia (n=28), indolent SM (n=14), smoldering SM (n = 2) or CMML (n=1). Median (range) age was 67 years (31–88), 56% were male and 88% had a KIT D816V mutation. Following treatment with avapritinib, a decrease in the proportion of patients with multifocal dense aggregates of MCs in BMBs was observed from 93% at screening to 50% by Week 8 (Table). Avapritinib treatment reduced the proportion of aberrant CD25+ and CD30+ MCs in BMBs by Week 8 and Week 24 (Table). In BMAs, avapritinib reduced the mean MC burden from 11% of total nucleated cells at screening to 2% at Week 8 and by Week 24, with reduced proportions of immature and spindle-shaped MCs (Table). Of 9 patients with circulating MCs at screening and post-screening sample measurements (6 with SM with associated hematologic neoplasm diagnoses and 3 with MCL), 8 had no detectable MCs in PB by Week 8. The proportion of patients with fibrosis in BMBs decreased from 96% (178/186) at screening to 90% (142/158) at Week 8 to 84% (103/123) through week 24, and MF scores were reduced during avapritinib treatment in those patients presenting with increased fibrosis at screening (Table). Image:Summary/Conclusion: Patients treated with avapritinib were observed to have rapid (Week 8) and marked (Week 24) reductions in neoplastic BM MCs with a return to a normal morphologic appearance and immunophenotype. This was accompanied by an improvement of fibrosis and a decrease in circulating MCs. These improvements in disease histopathology provide further support that treatment with this highly selective and potent KIT D816V inhibitor is disease modifying in AdvSM.